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Background The assessment of patients with suspected deep vein thrombosis (DVT) remains challenging despite current diagnostic algorithms. 99m Tc-labelled DI-DD3B6/22-80B3 Fab´ fragments ( 99m Tc-DI-80B3, ThromboView®) is a novel diagnostic test that uses a radiolabelled humanized monoclonal antibody fragment specific for the D-dimer region of cross-linked fibrin to detect DVT. This test has an anatomic component to locate DVT and a functional component to differentiate acute (newly formed) thrombus from inactive (old) thrombus. Methods In a multi-centre prospective cohort trial we investigated the diagnostic accuracy and safety of 99m Tc-DI-80B3 in consecutive patients with suspected DVT who had the diagnosis confirmed or excluded by venography. Results We enrolled 94 patients with suspected DVT of whom 12 did not have 99m Tc-DI-80B3 imaging, leaving 82 patients for the safety analysis. Of these patients, there were 16 with non-evaluable imaging (11 venography, 7 99m Tc-DI-80B3, both in two patients) leaving 66 patients for the accuracy analysis. 99m Tc-DI-80B3 imaging was well-tolerated: 2 patients developed urticaria; none developed serious adverse events. For proximal DVT, the sensitivity (84.2%; 95% confidence interval [CI]: 62.4–94.5) and specificity (97.6%; CI: 83.3–99.4) were highest when the combined 0.25-hour and 3-hour 99m Tc-DI-80B3 images were used. The accuracy was lower for distal DVT, irrespective of the images used. There were insufficient patients to comment on the accuracy of 99m Tc-DI-80B3 imaging for suspected recurrent DVT. Conclusions 99m Tc-DI-80B3 (ThromboView®) is a novel diagnostic modality for patients with suspected DVT with a promising accuracy and safety profile that justifies additional clinical development in diagnostic accuracy and clinical management studies.

The purpose of this study was to examine the effects of metabolic syndrome (MS) features on arterial elasticity of the large and small arteries in apparently healthy adults, to examine the effect of clustered features of MS, and to determine which features are most predictive of large and small artery elasticity. The subjects for this study consisted of 126 men and women, age 45 years and older. The subjects rested supine while pulse contour analysis was measured from the radial artery by using an HDI/Pulsewave CR-2000 instrument (Hypertension Diagnostic, Inc) to assess arterial elasticity in the large and small arteries. Medical history was obtained along with body mass index, waist circumference, body surface area, and blood pressure. Large artery elasticity was lower (p=0.002) in subjects with hypertension (12.7 ∓4.3 mL/mm Hg × 10) than in those with normotension (15.0 ∓4.2 mL/mm Hg × 10; mean ∓ SD), and small artery elasticity was lower (p=0.001) as well (3.9 ∓2.3 mL/mm Hg × 100 vs 5.3 ∓2.5 mL/mm Hg × 100). Large artery elasticity was lower (p=0.02) in obese subjects (12.2 ∓4.9 mL/mm Hg × 10) than in nonobese subjects (14.2 ∓4.5 mL/mm Hg × 10), and large artery elasticity was lower (p=0.04) in subjects with abdominal obesity (12.2 ∓4.5 mL/mm Hg × 10) than in those without (14.5 ∓4.8 mL/mm Hg × 10). Large artery elasticity decreased as the number of features of MS increased (p2 =0.37, p=0.003, SEE = 3.60 mL/mm Hg × 10), and hypertension was a predictor of small artery elasticity (R =0.53, R 2 =0.28, p=0.001, SEE = 2.12 mL/mm Hg × 100). Hypertension and obesity are the features of MS that are most predictive of impairment in large and small artery elasticity in apparently healthy middle-aged and older adults. Furthermore, impairment in large artery elasticity is more evident in subjects with at least three features of MS.

Glucocorticoids are extensively used in anti-inflammatory therapy and may contribute to the normal regulation of lymphopoiesis. This study utilized new information about the early stages of lymphopoiesis in mouse and man to determine precisely which cell types are hormone sensitive. Cycling B lineage precursors were depleted in dexamethasone-treated mice, while mature, non-dividing CD45R(Hi) CD19(Hi) lymphocytes, myeloid progenitors and stem cells with the potential for lymphocyte generation on transplantation were spared. Lineage marker-negative (Lin(-)) IL-7R(+) Flk-2(+) pro-lymphocytes also declined, but not as rapidly as the terminal deoxynucleotidyl transferase-positive cells within an early Lin(-) c-kit(Hi) Sca-1(Hi) fraction of bone marrow. Hormone-sensitive cells with additional properties of early lymphoid progenitors (ELP) were identified within the same Lin(-) c-kit(Hi) Sca-1(Hi) subset using human mu transgenic mice and recombination-activating gene 1 (RAG1)/green fluorescent protein knock-in animals. Furthermore, cells with a recent history of RAG1 expression were more glucocorticoid sensitive than mature lymphocytes in marrow and spleen. Lymphocyte progenitors in mice bearing a human bcl-2 transgene were protected from dexamethasone treatment. However, isolated progenitors from either wild-type or bcl-2 transgenic mice were directly sensitive to the hormone in stromal cell-free cultures, suggesting that additional factors must determine vulnerability to glucocorticoids. B lineage lymphocyte precursors were found to be abnormally elevated in the bone marrow of adrenalectomized or RU486-treated mice. This suggests that glucocorticoids may normally contribute to steady-state regulation of lymphopoiesis. Finally, parallel studies revealed that the earliest events in human lymphopoiesis are susceptible to injury during glucocorticoid therapy.

In a previous study of the prevention of venous thromboembolism after total knee replacement, the efficacy of ximelagatran, an oral direct thrombin inhibitor that does not require monitoring of coagulation or dose adjustment, was found to be similar to that of warfarin at a dose of 24 mg of ximelagatran twice daily. The purpose of the present study was to determine whether a higher dose of ximelagatran is superior to warfarin.This randomized, double-blind trial compared a regimen of 7 to 12 days of oral ximelagatran, at a dose of 24 or 36 mg twice daily, starting the morning after surgery, with warfarin therapy started the evening of the day of surgery. The composite end point of venous thromboembolism and death from all causes and the incidence of bleeding were the primary outcome measures.Among the 1851 patients in the efficacy analysis, oral ximelagatran at a dose of 36 mg twice daily was superior to warfarin with respect to the primary composite end point of venous thromboembolism and death from all causes (20.3 percent vs. 27.6 percent; P=0.003). There were no significant differences between these two groups with respect to major bleeding (incidence, 0.8 percent and 0.7 percent, respectively), perioperative indicators of bleeding, wound characteristics, or the composite secondary end point of proximal deep-vein thrombosis, pulmonary embolism, and death (2.7 percent vs. 4.1 percent; P=0.17).The efficacy of oral ximelagatran, administered starting the morning after total knee replacement, was superior to that of warfarin for prevention of venous thromboembolism. Rates of hemorrhagic complications with the two drugs were similar.

A multicenter, double-blind, randomized, placebo-controlled, parallel study was conducted to compare the efficacy and safety of cilostazol 100 mg and 50 mg, both administered twice daily, with that of placebo in patients with moderately severe intermittent claudication (IC) secondary to peripheral arterial disease. A total of 394 subjects 40 years of age or older with chronic, stable, symptomatic IC received cilostazol 100 mg twice daily, 50 mg twice daily, or placebo for 24 weeks. Subjects receiving cilostazol 100 mg twice daily experienced a 21% net improvement in maximal walking distance (MWD) compared with placebo subjects (p = 0.0003) and a 22% net improvement in distance walked to the onset of symptoms (PFWD) (p = 0.0015). Subjects who received cilostazol 50 mg twice daily also benefited from therapy, but not to a statistically significant degree (7% and 11% improvement in MWD and PFWD, respectively). Quality-of-life and functional status assessments corroborated these objective results. Cilostazol, in particular 100 mg twice daily, significantly improves symptoms in patients with IC.

Phosphofructokinase deficiency is a rare disorder with less than 100 reported cases; the contribution of altered glucose metabolism in other tissues to the pathogenesis of the disease is not fully understood. The authors present a unique case of portal and mesenteric vein thrombosis in a 43-year-old man with a known case of phosphofructokinase deficiency.

Background: Patients undergoing hip or knee joint replacement are at risk for venous thromboembolic complications for up to twelve weeks postoperatively. We evaluated the efficacy and safety of a prolonged post-hospital regimen of enoxaparin, a low-molecular-weight heparin, in this patient population. Methods: Following elective total hip or knee replacement, 968 patients received subcutaneous enoxaparin (30 mg twice daily) for seven to ten days, and 873 were then randomized to receive three weeks of double-blind outpatient treatment with either enoxaparin (40 mg once daily) or a placebo. The primary efficacy end point was the prevalence of objectively confirmed venous thromboembolism or symptomatic pulmonary embolism during the double-blind phase of treatment. Results: Of the 873 randomized patients, 435 underwent elective total hip replacement and 438 underwent elective total knee replacement. Enoxaparin was superior to the placebo in reducing the prevalence of venous thromboembolism in patients treated with hip replacement: 8.0% (eighteen) of the 224 patients treated with enoxaparin had venous thromboembolism compared with 23.2% (forty-nine) of the 211 patients treated with the placebo (p < 0.001; odds ratio, 3.62; 95% confidence interval, 2.00 to 6.55; relative risk reduction, 65.5%). Enoxaparin had no significant benefit in the patients treated with knee replacement: thirty-eight (17.5%) of the 217 patients treated with enoxaparin had venous thromboembolism compared with forty-six (20.8%) of the 221 patients treated with the placebo (p = 0.380; odds ratio, 1.24; 95% confidence interval, 0.76 to 2.02; relative risk reduction, 15.9%). Symptomatic pulmonary embolism developed in three patients, one with a hip replacement and two with a knee replacement; all had received the placebo. There was no significant difference in the prevalence of hemorrhagic episodes or other types of toxicity between the enoxaparin and placebo-treated groups. Conclusions: Prolonging enoxaparin thromboprophylaxis following hip replacement for a total of four weeks provided therapeutic benefit, by reducing the prevalence of venous thromboembolism, without compromising safety. A similar benefit was not observed in patients treated with knee replacement.

Protein S is a vitamin K-dependent protein with anticoagulant properties. Case series have reported reduced plasma concentrations in patients with arterial thromboses, while other studies have reported increased levels in patients with coronary heart disease (CHD). The present study sought to clarify the relation between free protein S and risk of CHD. A prospective survey was conducted of 3000 men aged 50 to 61 years, free of clinical CHD at baseline. Free protein S was measured by commercial immunoassay. End-points recorded were sudden coronary death, first nonfatal and fatal myocardial infarction (MI), surgical intervention for symptomatic, angiographically demonstrated CHD, and all-causes mortality. Statistical analysis employed univariate incidence rate ratios followed by Cox proportional hazards regression. There were 168 CHD events recorded during 21,000 person−years of risk. Mean free protein S concentration was 6% higher in those who developed CHD than in the remainder, the crude hazard ratio (HR) for a one standard deviation (S.D.) increase in free protein S being 1.25 (95% CI, 1.08–1.25). Free protein S was associated with cholesterol concentration and other conventional CHD risk factors. In multivariate regression analysis, after adjustment for conventional CHD risk factors a 1 S.D. increase in free protein S was associated with a HR of 1.15 (0.98–1.35) for CHD, of borderline conventional statistical significance. This association of free protein S with risk of CHD may reflect effects of plaque-destabilising inflammatory activity on protein S levels.

Orgaran (danaparoid sodium injection) is a novel antithrombotic agent. Early studies suggest that this compound may be beneficial in preventing deep vein thrombosis in predisposed patients. This multicenter, randomized, assessor blinded, clinical trial compared subcutaneous danaparoid with warfarin for the prevention of deep vein thrombosis in patients undergoing hip replacement surgery. Bilateral venography was used to detect thrombi. Patients also underwent follow-up examinations 1, 2, and 3 months after discontinuation of the study to determine the after effects of treatment. Nearly 27% of patients who received warfarin and 14.6% of patients who received danaparoid developed deep vein thrombosis, a risk reduction of 46%. The absolute difference in the incidence of deep vein thrombosis was 12.3% in favor of danaparoid. The incidence of venographically documented proximal deep vein thrombosis was 1.5% for danaparoid and 4.1% for warfarin. These results demonstrate that danaparoid is more effective than warfarin in preventing deep vein thrombosis following hip replacement surgery. The preoperative administration of danaparoid does not increase surgical blood loss compared with warfarin.

Fibrinogen has emerged as a risk factor for coronary artery disease in men that equals cholesterol in importance. It is known to play an important role in reparative processes, and evidence is accumulating that fibrinogen/fibrin accumulates at the site of minimal vascular injury. Fibrinogen contributes significantly to blood viscosity and its adherence to endothelium may mediate progression of atheromatous lesions. This study was designed to examine a number of markers of risk in a consecutive series of cardiology patients undergoing coronary catheterizations over a 15-month period. This article examines the level of fibrinogen in relation to the number of reported coronary stenoses and disease severity in a series of Caucasian female patients (n = 101). Women were classified as diseased if they had at least 1 lesionor = 25% in the coronary anatomy and nondiseased if they had no lesionsor = 25%. The number of reported lesions correlates significantly with fibrinogen levels (r = 0.36, p = 0.0002). Women with fibrinogen levelsor = 283 mg/dl had a 3.2-fold increased risk (95% confidence interval 1.2 to 9.1) of having at least 1 stenosisor = 25% after adjusting for age and diabetic status. Smoking and body mass index did not differ by disease status and thus did not confound the finding. Mean fibrinogen levels showed a progressive positive association with increasing clinically defined vessel involvement (stenosisor = 50%).

The hypothesis that the combination of low-dose aspirin and warfarin therapy is more effective than aspirin alone in secondary prophylaxis after myocardial infarction is to be examined in the Coumadin Aspirin Reinfarction Study. This pilot study addressed the safety and anticoagulation effect of a fixed, low-dose combination in 114 patients (aged 64 +/- 8 years, 85% men) with stable coronary artery disease receiving 3 mg of warfarin plus 80 mg of aspirin daily for 8 weeks. The international normalized ratio (INR) was measured within 72 hours of initial therapy, and weekly. Of the 110 patients with evaluable INRs, 87 patients (79%) maintained the 3 + 80 mg combination, 19 (17%) had the dose reduced to 1 mg warfarin + 80 mg aspirin, and 4 (4%) discontinued therapy because of a confirmed INR of > or = 4.5. At steady state, patients had INRs of 1.48 +/- 0.41 (3 + 80 mg group) and 1.21 +/- 0.23 (1 + 80 mg group), and inter- and intra-patient variability (estimated by the mean of the between- and within-patient SDs at steady state) was 0.49 +/- 0.08 and 0.13 +/- 0.14, respectively. There was no apparent effect of age on INR distribution. Microscopic hematuria was the most frequent (20%) adverse clinical event, but was unrelated to the INR. Three patients required discontinuation of therapy because of bleeding events (persistent hematuria and epistaxis). A fixed low-dose combination of warfarin and aspirin results in a predictable and stable increase in the INR in a large proportion of patients with coronary artery disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trial results support the aggressive use of anticoagulant therapy to prevent systemic embolism in patients with acute myocardial infarction who are at high risk for embolism (e.g., anterior transmural infarction). Other patients at risk for systemic embolism include those with chronic left ventricular aneurysm, chronic dilated cardiomyopathy, and cardiac tumors. The role of antithrombotic therapy in these latter groups is incompletely resolved because of a lack of clinical trials. However, in view of the devastating consequences of systemic embolism, the documented effectiveness of antithrombotic therapy in other high-risk patients and the improved safety of long-term anticoagulant treatment in recent years, it may be prudent to use antithrombotic treatment unless contraindicated.

Although the efficacy of recombinant tissue-type Plasminogen activator (rt-PA) in acute myocardial infarction has been demonstrated, little formal dose-ranging information is available. This study examined the use of duteplase, the double-chain rt-PA subsequently used in the Third International Study of infarct Survival, in a multicenter trial of 267 patients with evolving acute myocardial infarction assigned to receive 1 of 6 weight-adjusted doses. The primary end point was infarct vessel patency after 90 minutes of drug infusion. Patency was defined as Thrombolysis in Myocardial infarction trial grade 2 or 3 perfusion, and was determined by an independent core laboratory masked to treatment assignment. Patency was present in 48% of patients receiving the lowest dose range and 78% of those receiving the highest, with an association between thrombolytic dose and patency (p = 0.009). The frequency of serious bleeding complications also correlated with the total dose of rt-PA infused (p = 0.003). Bleeding complications were primarily related to instrumentation; blood toss requiring transfusion or otherwise deemed clinically significant occurred in 12% of patients (central nervous system hemorrhage occurred in 1.1%). Thus, higher doses of rt-PA are associated both with increased efficacy and increased risk of serious bleeding complications. Weight-adjusted dosing may provide an optimal risk-benefit ratio for thrombolysis during acute myocardial infarction.

Protein C is a natural anticoagulant glycoprotein which prevents intravascular clot formation. Protein C functions as an anticoagulant when converted to an active serine protease (activated protein C). Activated protein C is formed at the site of the endothelial injury in response to blood clotting and helps limit the size of blood clots. We tested the hypothesis that by temporarily blocking the activation of intrinsic protein C, we could reduce subsequent surgical blood loss from a microvascular surgical wound. The formation of activated protein C was blocked systemically by intravenous administration of a monoclonal antibody (HPC4) which binds to circulating protein C and prevents its conversion to activated protein C. Domestic pigs were blindly pretreated with intravenous HPC4 or saline then underwent partial-thickness skin graft harvesting to create a reproducible microvascular wound. Blood loss was measured from each wound and the hemostatic effect of protein C blockade was compared to intravenous saline alone as well as to topical thrombin or thromboplastin. We found that blocking the activation of protein C significantly (P = 0.005) reduces surgical blood loss in this model by 27% compared to saline control animals. Intravenous HPC4 performed equally as well as topical thrombin or tissue thromboplastin. In addition, topical thrombin acted synergistically with HPC4 to reduce blood loss an additional 44% (P = 0.01) as compared to intravenous HPC4 or topical thromboplastin alone. Autopsies performed 1 week after HPC4 treatment showed no evidence of systemic thrombosis resulting from the protein C blockade. This study reveals that blocking the formation of the natural anticoagulant, activated protein C prior to surgery provides a systemic means of reducing capillary bleeding from vascular beds.

In this study, we assessed the clinical and economic consequences of using dalteparin as first-line prophylaxis for deep-vein thrombosis and pulmonary embolism in patients undergoing inpatient rehabilitation following total knee arthroplasty. The objective of the study was to demonstrate that dalteparin can be used effectively and safely in this indication. Using data abstracted from medical records of patients admitted to an Oklahoma rehabilitation center following total knee arthroplasty, we found the occurrence of thromboembolic and bleeding events in patients receiving dalteparin to be low. Results of this study also suggest that use of dalteparin in this indication could offer rehabilitation hospitals a valuable source of cost savings, without compromising patient care.

Protein S is a natural anticoagulant plasma protein; familial deficiency is associated with thrombotic complications. Since smoking carries an increased risk of myocardial infarction and stroke, we investigated the protein S system of men who smoke. In plasma, free protein S is functionally active and protein S bound to C4b binding protein is inactive. Male smokers (n = 24) have lower total protein S than nonsmokers (n = 24) (16.8 +/- 4.3 micrograms/ml versus 19.8 +/- 5.1 micrograms/ml, p less than 0.02). C4b binding protein levels are higher (p less than 0.05) in smokers (212 +/- 47 micrograms/ml versus 186 +/- 52 micrograms/ml). Free protein S is significantly lower in smokers (6.9 +/- 2.3 micrograms/ml versus 8.0 +/- 1.9 micrograms/ml, p = 0.02). These alterations in protein S may contribute to the thrombotic complications associated with smoking.

The use of cyclosporine has been associated with an increased incidence of thrombosis and endothelial cell perturbation. To explore possible mechanisms involved, we examined the effects of CSA on the activation of protein C by thrombomodulin. Cultured bovine aortic endothelial cell monolayers were incubated for 24 hr with a wide range of CSA concentrations. After removal of CSA and incubation with thrombin and purified protein C, thrombomodulin-dependent protein C activation was measured with an S-2238-based kinetic chromogenic assay. As compared to control, a significant fall in thrombomodulin activity occurred after 24-hr incubation with 100 (70.8 +/- 15.8%, P less than 0.05), 1000 (64.9 +/- 16.6%, P less than 0.05), or 10,000 (28.9 +/- 12.3%, P less than 0.05) ng/ml of CSA. A comparable inhibition of thrombomodulin activity was also observed in cultured renal artery endothelial cells (67.5 +/- 12.6%, P less than 0.05), after 24-hr incubation with 5000 ng/ml CSA. In cells incubated with 5000 ng/ml of CSA for 4 hr, thrombomodulin activity fell by almost 15% (85.6 +/- 8.3%, P less than 0.05) and tended to plateau between 7 hr (73.8 +/- 12.7%, P less than 0.05), and 24 hr of incubation (72.7 +/- 8.9%, P less than 0.05). These results indicate that CSA produces a time- and dose-dependent reduction in thrombomodulin activity of cultured endothelial cells, downregulating the protein C anticoagulant pathway, thereby increasing the risk of thrombosis.

The platelet-reactive monoclonal antibody 50H.19, its F(ab')2 fragments, and 99m-technetium (99m-Tc)-labeled fragments used in thrombus imaging were evaluated for their ability to cause platelet aggregation. The intact antibody caused a dose-dependent platelet aggregation in either platelet-rich plasma (PRP) or defined buffer solutions. The F(ab')2 fragments did not cause platelet aggregation except at high calcium concentrations. Neither stannous-ion-treated antibody fragments nor 99m-Tc-labeled antibody fragments caused platelet aggregation. The antibody-induced platelet aggregation was completely inhibited by 8-bromo-cAMP, caffeine, theophylline diltiazem, and staurosporin; partially inhibited by EDTA, EGTA, cytochalasin B, colchicine, aspirin, or indomethacin. Treatment of platelets with the intact 50H.19 antibody resulted in phosphorylation of a 40K dalton platelet protein, similar to that caused by treatment with phorbol myristate acetate (PMA). Phosphorylization of the 40K protein was not observed after treatment with either the 50H.19 F(ab')2 fragments or the calcium ionophore A23187.

Dabigatran, an oral once-daily unmonitored thrombin inhibitor, has been tested elsewhere using enoxaparin 40 mg once daily. We used the North American enoxaparin 30 mg BID regimen as the comparator. This was a double-blind, centrally randomized trial. Unilateral total knee arthroplasty patients were randomized to receive oral dabigatran etexilate 220 or 150 mg once daily, or enoxaparin 30 mg SC BID after surgery, blinded. Dosing stopped at contrast venography, 12 to 15 days after surgery. Among 1896 patients, dabigatran 220 and 110 mg showed inferior efficacy to enoxaparin (venous thromboembolism rates of 31% [P = .02 vs enoxaparin], 34% [P < .001 vs enoxaparin], and 25%, respectively). Bleeding rates were similar, and no drug-related hepatic illness was recognized. Dabigatran, effective compared to once-daily enoxaparin, showed inferior efficacy to the twice-daily North American enoxaparin regimen, probably because of the latter's more intense and prolonged dosing.

ObjectiveTo determine whether differences in vascular reactivity existed among normal weight, overweight, and obese older men and women, and to examine the association between abdominal fat distribution and vascular reactivity.MethodsEighty-seven individuals who were 60 years of age or older (age = 69 ± 7 yrs; mean ± SD) were grouped into normal weight (BMI < 25; n = 30), overweight (BMI ≥ 25 and < 30; n = 28), or obese (BMI ≥ 30; n = 29) categories. Calf blood flow (BF) was assessed by venous occlusion strain-gauge plethysmography at rest and post-occlusive reactive hyperemia.ResultsPost-occlusive reactive hyperemia BF was lower (p = 0.038) in the obese group (5.55 ± 4.67 %/min) than in the normal weight group (8.34 ± 3.89 %/min). Additionally, change in BF from rest to post-occlusion in the obese group (1.93 ± 2.58 %/min) was lower (p = 0.001) than in the normal weight group (5.21 ± 3.59 %/min), as well as the percentage change (75 ± 98 % vs. 202 ± 190 %, p = 0.006, respectively). After adjusting for age, prevalence in hypertension and calf skinfold thickness, change in BF values remained lower (p < 0.05) in obese subjects compared to the normal weight subjects. Lastly, the absolute and percentage change in BF were significantly related to BMI (r = -0.44, p < 0.001, and r = -0.37, p < 0.001, respectively) and to waist circumference (r = -0.36, p = 0.001, and r = -0.32, p = 0.002).ConclusionObesity and abdominal adiposity impair vascular reactivity in older men and women, and these deleterious effects on vascular reactivity are independent of conventional risk factors.

We have examined factor VIIa levels in consecutive consenting patients undergoing coronary angiography (n = 702) to determine if levels are related to the presence of coronary arterial narrowing and to the degree and extent of that narrowing. Both men and women with clinically defined coronary artery disease (> or = 50% stenosis in at least 1 vessel) had factor VIIa levels that were similar to men and women with less stenosis or normal coronary arteries.

Venous thromboembolic (VTE) disease consists of deep vein thrombosis and/or pulmonary embolism. Either low molecular weight heparin given subcutaneously or unfractionated heparin administered intravenously are used for the initial treatment. Simultaneously, warfarin therapy is initiated. Thrombolytic therapy plays a limited role. Following the initial heparin treatment, anticoagulation clinics provide an excellent means of monitoring the oral anticoagulation. Patient education is important and patients should be well versed in the basic features of oral anticoagulation. The duration of oral anticoagulation is dependent on a number of factors including the presence of inherited risk factors, bleeding risk and patient reliability. Residual thrombus in the affected vein may indicate the need for prolonged anticoagulation. The low intensity oral anticoagulation (INR 1.5-2.0) is useful in preventing recurrent thrombosis following the initial treatment period with full intensity oral anticoagulation.

Venous thromboembolism is a serious, frequent, and potentially fatal complication of major orthopedic surgery. Currently available pharmacologic agents for the prevention of venous thromboembolism in this high-risk population consist of the oral anticoagulants and the heparin family of antithrombotic agents (unfractionated heparin, low-molecular-weight heparin, heparinoids). These classes of agents interfere with the activity of both thrombin and factor Xa (or their respective zymogens) to varying degrees. Newer antithrombotic agents in various stages of development exert their antithrombotic effect through a more targeted mechanism of action. Direct factor Xa inhibitors and the newest class of antithrombotic agents, the indirect factor Xa inhibitors, the prototype of which is the synthetic pentasaccharide fondaparinux sodium, limit fibrin formation through their exclusive inactivation of factor Xa. Clinical data from venous thromboembolism prophylaxis trials in hip and knee replacement and hip fracture surgeries, including the recently completed fondaparinux phase II and phase III trials, indicate that selective antifactor Xa activity may improve the efficacy:safety ratio of antithrombotic therapies for the prevention of venous thromboembolism in high-risk major orthopedic surgery.

This study addressed several questions concerning age-related changes in human B lymphopoiesis. The relative abundance of pro-B, pre-B, immature, naive, and mature B cells among the CD19(+) lymphocyte fraction of human bone marrow was found not to change appreciably over the interval between 24 and 88 years of age. Moreover, proliferation of pro-B and large pre-B cells in adult marrow equaled that observed with fetal marrow specimens. Exceptionally low numbers of lymphocyte precursors were found in some marrow samples, and the values obtained were used to determine parameters that best reflect B lymphopoiesis. Cord blood always contained higher incidences of functional precursors than adult cells. However, sorted CD34(+) Lin(-) CD10(+) progenitors from cord blood and adult marrow had equivalent potential for differentiation in culture, and notable age-related changes were found in more primitive subsets. A recently described subset of CD34(+)CD38(-)CD7(+) cord blood cells had no exact counterpart in adult marrow. That is, all adult CD34(+)Lin(-)CD7(+)CD10(-) cells expressed CD38, displayed less CD45RA, and had little B-lineage differentiation potential. The CD7(+) fractions in either site contained progenitors for erythroid and natural killer (NK) lineages, and ones sorted from marrow expressed high levels of transcripts for the CD122 interleukin 2 (IL-2)/IL-15 receptor required by NK-lineage precursors. Dramatic changes in human B lymphopoiesis occur early in life, and more information is required to construct a probable sequence of differentiation events prior to the acquisition of CD10.

A young Native American woman presented with ischemia of the left lower limb resulting from embolic occlusion of the left common iliac artery and left femoral artery. The source of her emboli was aortic thrombus. The only underlying abnormality responsible for her hypercoagulability appeared to be hyperhomocysteinemia.

Introduction Cancer associated thrombosis is the second most common cause of mortality among patients with malignancy. While preventive low molecular weight heparin is effective in preventing venous thromboembolism (VTE), lack of agreement on risk stratification methods have precluded its widespread use. The most studied VTE prediction tool is the Khorana score, but it does not capitalize on the use of novel biomarkers. We aimed to evaluate the value of biomarkers in prediction of VTE among patients with active cancer receiving outpatient chemotherapy. Methods We prospectively collected pre-chemotherapy blood samples on adult patients with solid organ tumors. We excluded patients on anticoagulation and those unable or unwilling to consent. Along with demographics and cancer specific variables, potential novel predictors of VTE were selected a priori and included: coated platelets (CP), D dimer (DD), protein C (PC), fibrin monomers (FM), mean platelet volume (MPV), platelet microparticles (PMP). Type of cancer was grouped according to the Khorana score (Very high risk: Stomach, Pancreas; High risk: Lung, Gynecologic, Bladder, Testicular; Low/Moderate risk: all other sites). VTE events were adjudicated at 6 months of follow up. For all statistical analyses we used SAS 9.2 (SAS Institute Inc., Cary, NC, USA). A p value of Results We have recruited a total of 101 patients (mean + standard deviation age 59.7+11 years, 68% female), 20% of the 75 patients with complete follow up have developed a VTE. We found no significant association between the incidence of VTE and age, gender, or baseline Khorana score. The variables associated with incident VTE were: BMI (odds ratio [OR] 8.5 for BMI Conclusion Pre Chemotherapy level of Protein C is a potential biomarker for the incidence of VTE. We confirm that cancer type and BMI are predictors of cancer associated VTE. In addition, lower BMI is not usually recognized as a potential predictor of VTE in other prediction scores. We were underpowered to detect differences in the VTE incidence according to Khorana score. Finally, aspirin may have a role in outpatient cancer associated VTE prevention and deserves further investigation. Disclosures: Tafur: Stago Diagnostica: Research Funding. Rathbun:Stago Diagnostica: Research Funding.

When compared with older reports on the thromboembolic effects of high-dose oral contraceptives, new studies with low-dose oral contraceptives have a significantly reduced risk of thromboembolism. In the absence of risk factors such as smoking or inherited disorders predisposing to thrombosis, the modern low-dose oral contraceptive (50 micrograms of estrogen) is a safe and effective choice for contraception in women without symptoms who have family histories of sporadic thromboembolism. An intrauterine device or some form of barrier method is recommended for women who have a personal history of venous thrombus disease. The low-dose oral contraceptive may be a good choice in women taking oral anticoagulants because of the risk of teratogenic effects of anticoagulants and the risks of intraperitoneal bleeding associated with ovulation. In addition, oral contraceptives help diminish the excessive menstrual bleeding often seen in these women.Pregnancy and oral contraceptives (OCs) reduce the levels of the natural anticoagulant protein S and about 50% and 20%. respectively. Original work on the link between OCs and development of deep vein thrombosis and pulmonary embolism do not necessarily confirm an association, today since it included cohort studies of women using high estrogen OCs. Also, physicians tended to actively diagnose thrombophlebitis in women they knew were using OCs. Objective diagnostic measures, e.g., venography, were not used in the cohort studies. Decreased estrogen content of current OCs and a case control study design show the likelihood of thrombotic complications of OS use has decreased significantly. Women who have experienced an episode of venous thrombosis and are not on oral anticoagulation therapy should not use OCs, because as many of 30% experience a second episode. Women with a strong family history of thromboembolism and those with antiphospholipid antibodies who have experienced a thrombotic event should also not use OCs. Current or past use of low estrogen Ocs does not significantly increase the risk of myocardial infarction, but smoking does. Physicians doe not know, however, whether women who use an OC with at the most 30 mcg estrogen and who smoke are at greater risk than those who smoke but do not use OCs. Just one study suggests a possible association between OC use and mitral valve prolapse leading to a cerebrovascular accident. The likelihood of developing calf vein clots in women who use low-dose OCs appears to be reduced, if they use sequential compression stockings and subcutaneous low molecular weight heparin following surgery. Since OCs decrease the chance of serious bleeding during ovulation and of heavy menstrual flow, oral anticoagulation is not a contraindication to OC use. The risk of OC-associated thromboembolism is considerably lower than that of pregnancy-associated thromboembolism.

Heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP) weekly therapy was evaluated for safety and efficacy in selectively reducing LDL cholesterol levels. Weekly treatments (25) were given to high-risk hypercholesterolemic patients (n = 33) with screening LDL cholesterol levels > 160 mg/dl despite prior diet and drug therapy. Lipids, lipoprotein cholesterol, apolipoproteins A-l and B, and fibrinogen were measured on plasma samples before and after treatment. Mean plasma volume treated was 2.66 liters and mean treatment duration 1.7 hours. Therapy complications were infrequent and were primarily vascular access problems or hypotension. Treatment goals were > 30% LDL cholesterol reduction with each treatment. In 98% of 686 HELP treatments, LDL cholesterol levels were reduced > or = 30%. Mean LDL cholesterol levels were reduced 111.0 mg/dl (54%) with a time-averaged decrease of 39% over a 25-week course. Mean HDL cholesterol was reduced only 6.2 mg/dl (15%). Total cholesterol (134.4 mg/dl; 47% decrease) and apolipoprotein B (88.7 mg/dl; 53% decrease) levels were also reduced. Fibrinogen decreased 158.2 mg/dl (58%) without bleeding complications. HELP therapy can safely and selectively remove plasma LDL cholesterol, producing consistent reductions in LDL cholesterol, total cholesterol and apolipoprotein B levels.

Significant advances have been made in defining the regulatory mechanisms that control blood clotting. These are reviewed, with special attention to the functions of the natural inhibitors antithrombin III, protein C, and protein S. Congenital deficiencies of these inhibitors as well as acquired abnormalities, such as defective fibrinolysis, and their role in promoting thrombosis are also discussed, as are thrombotic complications of pregnancy. Pregnancy decreases levels of protein S to 40% to 50% of normal levels. The decrease occurs early in pregnancy and persists into the postpartum period; it appears to be a hormonal rather than a dilutional effect. It is not known whether the thrombotic risk associated with pregnancy is increased in women who are congenitally deficient in protein S. Oral contraceptives decrease levels of protein S by about 20%. Women with a personal or family history of thrombosis should be evaluated for predisposing conditions before they start an oral contraceptive, as should women taking oral contraceptives who develop deep venous thrombosis.Most people who experience venous thrombosis have normal hemostasis. Some people have inherited deficiencies of protein C, protein S, and antithrombin iii. They tend to have deep venous thrombosis which increases their risk for pulmonary emboli. Some acquired disorders which predisposes people to thrombosis include defective fibrinolysis which often occurs after surgery or infection, Trousseau's syndrome (excessive coagulant activity linked with adenocarcinoma), and lupus anticoagulant which is an immunoglobulin G or M antibody directed against negatively charged phospholipids. Hormones and probably not a dilution effect reduces free and bound protein S levels during pregnancy. Functional protein S activity is still 40-50% below normal levels 1-3 days after delivery. This decrease appears to protect against bleeding but does have venous thrombosis and pulmonary emboli during pregnancy as side effects. Non-oral-contraceptive (OC) users have greatly higher protein S levels than do OC users (28.6 mcg/ml vs. 24.3 mcg/ml; p.005) which gives more credence to the belief that hormones are responsible for the fall in protein S activity during pregnancy. OCs reduce free and total protein S levels almost 20%. Smoking may even further reduce these levels in women during pregnancy and who use Ocs. Women who have had venous thrombosis should not use OCs. Physicians should also consider family history especially age of affected family member, severity of thrombotic episodes, and the clinical setting. They should look for an underlying abnormality in patients who develop thrombosis while using OCs. If thrombosis develops during pregnancy, physicians should call for a venogram, venous duplex scanning, and, if required, invasive tests. The most sensible treatment is intravenous heparin for 5-7 days then therapeutic doses of heparin. Heparin therapy should stop before delivery and be reinstituted shortly thereafter and continued throughout the postpartum period. Physicians should take extra precautions when performing surgery on an OC user.

Compression ultrasonography has a high negative predictive value for deep vein thrombosis in symptomatic outpatients. Limited data are available on factors influencing positive predictive value. The objective of this study was to evaluate the positive predictive value of compression ultrasonography according to the anatomic site of vein noncompressibility.We performed a prospective cohort study of 756 consecutive outpatients with suspected first-episode deep vein thrombosis. Compression ultrasonography was performed at the initial visit: results were abnormal if a noncompressible segment was identified or normal if all segments were fully compressible. Venography was performed in patients with abnormal compression ultrasonography results. Positive predictive value was determined according to the site of noncompressibility: common femoral vein only, popliteal vein only, or both sites. Venography was the reference standard for the presence of deep vein thrombosis.Positive predictive value was 16.7% (95% confidence interval, 0.4%-64.1%) for noncompressibility isolated to the common femoral vein compared with 91.3% (95% confidence interval, 72.0%-98.9%) for the popliteal vein only and 94.4% (95% confidence interval, 72.7%-99.9%) for both sites (P.001). Of 15 patients with isolated noncompressibility of the common femoral vein, 8 (53%) had pelvic neoplasm or abscess compared with 2 (5%) of 42 with noncompressibility of the popliteal vein only and 6 (13%) of 47 with noncompressibility of both sites (P.001).The positive predictive value of noncompressibility isolated to the common femoral vein is too low to be used alone as the diagnostic end point for giving anticoagulant therapy. Noncompressibility isolated to the common femoral vein is a diagnostic marker for pelvic disease.

An endothelial cell-associated cofactor that greatly enhances the rate of protein C activation by thrombin has recently been described. The observation that the cofactor binds thrombin with unusually high affinity (K(d) = 0.5 nM) suggested that low level thrombin infusion into dogs might lead to the selective activation of protein C. Infusion of thrombin (1 U/min per kg body wt) into the jugular vein of dogs leads to the formation of a systemic anticoagulant activity within 5 min of starting the infusion. The plasma has a prolonged partial thromboplastin time and Factor X(a) clotting time, but there is no change in the thrombin clotting time. The systemic anticoagulant activity is identified as activated protein C for the following reasons: (a) anti-canine activated protein C IgG antibodies inhibit the anticoagulant activity; (b) the anticoagulant activity can be partially purified from the plasma of dogs infused with thrombin by barium citrate adsorption; (c) the anticoagulant has chromatographic properties on QAE Sephadex indistinguishable from those of activated protein C, and (d) the rate at which this anticoagulant is inhibited in citrated canine plasma is identical to that of canine activated protein C. The in vivo activation of protein C appears to be receptor mediated since it occurs at low thrombin concentration and since it can be progressively inhibited by simultaneous infusion of diisopropylphospho-thrombin with thrombin. The activation of protein C at low levels of thrombin is selective, since neither the platelet count nor the Factor V levels are altered. Thrombin infusion leads to an elevation in circulating plasminogen activator levels. This appears to be mediated through the activation of protein C since coinfusion of diisopropylphospho-thrombin with thrombin inhibits the increase in plasminogen activator levels. Pretreatment of dogs with dicumarol blocks both the formation of anticoagulant activity and the rise in plasminogen activator. When the dicumarol-treated dogs are supplemented with isolated protein C and thrombin is infused, the anticoagulant activity again appears and the circulating levels of plasminogen activator are again elevated. These studies illustrate that low levels of thrombin in vivo can activate protein C, which in turn can inhibit blood coagulation and initiate fibrinolysis by elevating circulating plasminogen activator levels.

We speak very frequently of the normal clotting time. In a glass tube?... Glass tubes have held the center of the stage for quite a long time but the process of clotting is now observed in plastic ...

An extracellular β-galactosidase with an activity optimum at about p H 4 was found to occur in the filtrates of Neurospora crassa strain 74A when this mold was grown on certain sugars. This activity accounted for a substantial portion of the β-galactosidase activity in the culture. The β-galactosidase in the medium appeared to be a secreted, extracellular enzyme, not a product of cell lysis. The extracellular activity was found to have physical and kinetic properties similar to those of an intracellular β-galactosidase previously found in Neurospora . Some conditions for the production and concentration of the enzyme are described.

Proteins C and S are two vitamin K-dependent plasma proteins that work in concert as a natural anticoagulant system. Activated protein C is the proteolytic component of the complex and protein S serves as an activated protein C binding protein that is essential for assembly of the anticoagulant complex on cell surfaces. The anticoagulant activity is expressed through the selective inactivation of Factors Va and Villa. Many patients deficient in proteins C and S have been described and have an associated thrombotic tendency, but not all heterozygous protein C and S deficient individuals experience thrombotic complications. Multiple mechanisms and/or drugs can lead to acquired deficiencies of these proteins: oral anticoagulation, liver disease, DIC and in the case of protein S, lupus erythematosus, nephrotic syndrome, pregnancy and certain hormones. The anticoagulant activity of protein C decreases rapidly after administration of warfarin (i.e., with a time course similar to Factor VII). This rapid decrease may lead to a transient imbalance and contribute to coumarin induced skin necrosis. Protein S antigen levels do not decrease as rapidly, but protein S functional levels are often low in patients with an acute thrombus. The discrepancy between antigen and function results from elevations in C4b-binding protein, which complexes reversibly with protein S. Unlike free protein S, the complex does not function in the anticoagulant pathway. The available information all suggest that deficiency of protein C and protein S should be considered a risk factor contributing to recurrent thrombotic disease and that the function of these proteins is altered by many common clinical conditions which have associated an increased risk of thrombosis.

Protein S is an antithrombotic plasma protein that serves as a cofactor for another plasma protein, activated protein C. Protein S is required for the expression of the anticoagulant effect of activated protein C, which inhibits blood clotting at the levels of factors V and VIII in the blood-clotting cascade. We postulated that patients deficient in protein S would have inadequate regulatory control of the clotting cascade and would be prone to thrombotic disease in a manner similar to that of patients congenitally deficient in protein C. To determine whether protein S deficiency is associated with recurrent thrombosis, we developed a functional assay for the plasma protein. With this assay, the protein S activity of normal persons ranges from 63 to 160 per cent. Using this test, we have now identified six unrelated persons with severe recurrent venous thrombosis who were deficient in protein S, with levels between 15 and 37 per cent while they were not receiving warfarin therapy. Our data suggest that the determination of protein S levels will be useful in the evaluation of patients with recurrent thrombosis.

The recently developed coagulolysis assay was utilized in conjuction with fibrinogen uptake scanning to monitor 91 of 111 consecutive orthopedic patients scheduled for hip surgery or total knee replacement. Sixteen patients had abnormal coagulolysis assays and positive scans. Venography was performed in 15 of these patients, and deep vein thrombosis was documented in 12. Five patients developed pulmonary emboli, including one with negative venogram. Thus, over 80% of the patients in which both the coagulolysis assay and the fibrinogen scan were abnormal had additional documentation of deep vein thrombosis. In 41 patients, the coagulolysis assay was negative. Venograms were not routinely performed in this group. However, 3 patients developed pulmonary emboli indicating that deep vein thrombosis developed in this group. Only one patient had a normal coagulolysis with a positive fibrinogen scan. Venography documented a deep vein thrombosis. Thirty-three patients who had normal coagulolysis assays and negative fibrinogen scans also had no evidence of deep vein thrombosis or pulmonary embolism. The coagulolysis assay appears to be a safe, noninvasive study for the detection of deep vein thrombosis. There was only a one per cent false-negative incidence.